PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle

Mohaned Benzarti, Laura Neises, Anais Oudin, Christina Krötz, Elodie Viry, Ernesto Gargiulo, Coralie Pulido, Maryse Schmoetten, Vitaly Pozdeev, Nadia I Lorenz, Michael W Ronellenfitsch, David Sumpton, Marc Warmoes, Christian Jaeger, Antoine Lesur, Björn Becker, Etienne Moussay, Jerome Paggetti, Simone P Niclou, Elisabeth LetellierJohannes Meiser*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Modeling tumor metabolism in vitro remains challenging. Here, we used galactose as an in vitro tool compound to mimic glycolytic limitation. In contrast to the established idea that high glycolytic flux reduces pyruvate kinase isozyme M2 (PKM2) activity to support anabolic processes, we have discovered that glycolytic limitation also affects PKM2 activity. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near-complete block of PKM2 to divert carbons toward serine metabolism. Simultaneously, TCA cycle flux is sustained, and oxygen consumption is increased, supported by glutamine. Glutamine not only supports TCA cycle flux but also serine synthesis via distinct mechanisms that are directed through PKM2 inhibition. Finally, deleting mitochondrial one-carbon (1C) cycle reversed the PKM2 block, suggesting a potential formate-dependent crosstalk that coordinates mitochondrial 1C flux and cytosolic glycolysis to support cell survival and proliferation during nutrient-scarce conditions.

Original languageEnglish
Article number113868
JournalCell Reports
Volume43
Issue number3
Early online date28 Feb 2024
DOIs
Publication statusPublished - 26 Mar 2024

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